A Phase 2, Open Label, Multicenter, Randomized Trial Comparing Tivozanib in Combination With mFOLFOX6 to Bevacizumab in Combination With mFOLFOX6, In Stage IV Metastatic Colorectal Cancer (mCRC) Subjects

Inclusion Criteria:

- Documented diagnosis of metastatic colorectal cancer

- One measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

- No prior systemic chemotherapy for advanced colorectal cancer; no fluorouracil
containing adjuvant therapy in previous 6 months

- Eastern Cooperative Oncology Group (ECOG) status of 0 or 1

Exclusion Criteria:

- Any prior Vascular Endothelial Growth Factor (VEGF)-directed therapy or any other
agent or investigational agent targeting the VEGF pathway

- Primary Central Nervous System (CNS) malignancies or CNS metastases

- Hematologic abnormalities:

- Hemoglobin < 9.0 g/dL,

- ANC < 2000 per mm3,

- Platelet count < 100,000 per mm3,

- Prothrombin (PT) or Partial Thromboplastin Time (PTT) > 1.5 X Upper Limit of
Normal (ULN)

- Serum chemistry abnormalities:

- Total bilirubin > 1.5 X ULN,

- Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2.5 X
ULN,

- Alkaline phosphatase > 2.5 X ULN,

- Serum albumin < 2.0 g/dL,

- Creatinine > 1.5 X ULN,

- Proteinuria > 2+ by urine dipstick

- Significant cardiovascular disease

- Significant thromboembolic or vascular disorders within 6 months prior to
administration of first dose of study drug

- Non-healing wound, bone fracture, or skin ulcer

- Inadequate recovery from any prior surgical procedure or major surgical procedure
within 8 weeks prior to administration, or anticipation of major surgical procedure
during the course of the study

- History of significant gastrointestinal (GI) toxicity, diarrhea, or stomatitis within
the last 6 weeks

- An active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or
other gastrointestinal condition with increased risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 4 weeks prior to administration of first dose of study drug

- Serious/active infection or infection requiring antibiotics

- Significant bleeding disorders within 6 months prior to administration of first dose
of study drug

- Active second primary malignancy, other than non-melanoma skin cancers,
non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular
carcinoma in situ of the breast. Subject is not considered to have a currently active
malignancy if they have completed anti-cancer therapy and have been disease free for
> 5 years

- History of allergic reactions, or intolerance, attributed to compounds of similar
chemical or biologic composition to 5-fluorouracil, history of Grade 3
hypersensitivity to oxaliplatin, history of allergic reaction to folic acid

- Female subject is pregnant or lactating

- Known history of genetic or acquired immune suppression disease including Human
Immunodeficiency Virus (HIV); subjects on immune suppressive therapy for organ
transplant

- Inability to swallow pills, malabsorption syndrome or gastrointestinal disease, major
resection of the stomach or small bowel, or gastric bypass

- Uncontrolled neuro-psychiatric disorder or altered mental status

- Peripheral neuropathy ≥ Grade 2

- Participating in another interventional protocol